Anti-depressant pharmaceutical composition containing n-{8 3,4di(alkoxycarbonyl)cinnamyl{9 {0 iminodibenzyl as the active ingredient

ABSTRACT

WHEREIN R is a lower alkyl group, or a non-toxic acid addition salt thereof as the active ingredient.   Anti-depressant pharmaceutical composition containing N-(3,4di(alkoxycarbonyl)cinnamyl)iminodibenzyl of the formula:

United States Patent Calm et al.

[ 51 June 13, 1972 Societe d'Etude et d'Exploltetion de Marques, Paris, France [22] Filed: Oct. 13,1969

[21] Appl. No.: 870,738

Related US. Application Data [62] Division of Ser. No. 624,729, March 2|, 1967, Pat.

[30] Foreign Application Priority Data March 25, 1966 Great Britain 13,362/66 [51] [58] Field of Search 424/244 [56] References Cited UNTI'ED STATES PATENTS 2,666,051 l/l954 Hafliger et al. ........................424/239 Primary Examiner-Stanley .l. Friedman Attorney-McClure, Weiser & Millman ABSTRACT Anti-depressant pharmaceutical composition containing N- [3,4-di(alkoxycarbonyl)cinnamylIiminodibenzyl of the forwherein R is a lower alkyl group, or a non-toxic acid addition salt thereof as the active ingredient.

5 Claims, No Drawings in which R represents a lower alkyl group, and their nontoxic acid addition salts. Also, the invention provides the pharmaceutical composition comprising the above defined compound with a pharmaceutically acceptable carrier.

More particularly, the present invention provides i i-{3,4- di( ethoxycarbonyl )cinnamyl] giminodibenzyl of formula:

The new compounds may be prepared by a process which comprises reacting a 3,4-di[(lower alkoxy)carbonyl)cinnamic acid halide in an inert solvent with iminodibenzyl at an elevated temperature. For example, N-3,4-[di(ethoxycarbonyl)cinnarny1]iminodibenzyl may be prepared by reacting 3,4- di(ethoxycarbonyl)-cinnamic acid chloride in benzene solution with iminodibenzyl, according to the following reaction:

CH=CHCOCl In the resulting compound, the free phenolic functions in caffeic acid are blocked with ethoxycarbonyl groups. These blocking groups are relatively easy to remove even in vivo to give the free 3,4-dihydroxycinnamyl derivative.

The invention is illustrated by the following example:

EXAMPLE 3.4 g. (0.0] mole) of 3,4 li(ethoxycarbonyl)cinnamic acid chloride dissolved in 10 ml. of anhydrous benzene were introduced into a 50 ml. flask. 1.95 g. (0.01 mole) of iminodibenzyl were added and the mixture heated under reflux for 24 hours, afier which, the solution was filtered and the benzene evaporated under reduced pressure. The residue was dissolved in hot alcohol (about 15 ml). On cooling, the N- [3,4-di(ethoxycarbonyhcinnamylliminodibenzyi which crystallized out, was filtered 0E. The crystals obtained were recrystallized dissolving them in the minimum amount of hot alcohol and filtering the solution. On cooling, white crystak of N-[ 3,4-di(ethoxycarbonyl )-cinnamyl -iminodibenzyl were obtained, which, on filtering and drying in an oven at C. gave 4.1 g. (82 percent of the theoretical yield) of white crystals melting at 153' C; these were insoluble in water and soluble in acetone.

The therapeutic effectiveness of one of the compounds of the invention is illustrated by the following tests.

I Antagonistic eifect relative to Reserpine in rats The purpose of this test, which was conducted with white male rats, was to compare the effect of the compound of the invention with that of Tofranil [N-(y-dimethylaminopropyhiminobenzyl], known for its antagonistic effect relative to reserpine, on the development of ptosis, the foetal attitude and the body temperature afler injection of reserpine.

Twenty rats each weighing about grams, divided into 5 groups, were used for this study: Two groups received Tofranil administered orally in dosages of i0 and 25 mg/kg, two other groups received the equivalent amounts of the new compound administered in the same manner, and the last group received only isotonic saline. Ninety minutes after these materials had been administered all the rats were given an intraperitoneal injection of 2.5 mg/kg of reserpine. Checks were carried out 2, 4, 6 and 24 hours afler this injection. The results are listed in the tables.

Table lshows, as a function of time. the number of animals showing ptosis, and the mean intensity of this symptom in a group. It was found that Tofranil is ineffective at a dosage of 10 mg/kg and that at 25 mg/kg it encourages both the appearance and the regression of the symptom. On the other hand, the new compound at a dosage of IO rug/kg reduced the phenomenon, and, at 25 mglkg, there was, in addition, a very clear efl'ect on the time of appearance and time of regression, so that the ptosis was only present in halfthe animals and only after 4-6 hours.

Table II (foetal attitude) leads to similar observations. The ingestion of 25 mg/kg of the new compound practically completely prevented this change of posture, and a dosage of i0 rug/kg is only a little less effective; the efl'ect of Tofranil is doubtful.

Table II] shows the change in body temperature as a function of time. Tofranil has an antagonistic efl'ect on the hypothermia induced by reserpine; this efi'ect is proportion to the dose administered. The effect of the compound of the invention at 10 mg/kg is very marked, but at 25 mg/ltg it is practically nil on the first three occasions of examination, and the effect is only observed after 24 hours.

TABLE L-DEVELOPMENT 0F PTOSIB AB A FUNCTION OF TIME Tut compound administered 4 hours 2 hours fihours 241mm mg. g Compound according to invention at 25 mgJkg I 2 I. 4 2 l 4 L5 1 Average intensity. I Number oi rats exhibiting ptosis within each group tested.

Finally, the diarrhoea symptoms caused by reserpine are completely absent in the group which had received 25 mg/kg of the new compound, and limited in the case of those treated with 10 mg/kg. No clear effect was observed with Tofranil.

It follows from this test, which is specific for demonstrating the thymoleptic effect of Tofranil, that the compound of the invention is, in the case of rats, endowed with the same type of activity, but more intense, than that ofTofranil.

Change in Temperature in C as a Function of Time Compound administered 2 hours 4 hours 6 hours 24 hours Reserpine 0.37 0.40 0.97 l.l

Tofranil at l0 mg/kg Tofranil at 25 mg/kg Compound according to the invention, at

10 mg/kg Compound accord ing to the invention, at

25 mg/kg 2. meet on the motor activity of mice The effect of the compound of the invention on the spontaneous motor activity of mice, with and without a preliminary dose of amphetamine, was compared with that of Tofranil. The following technique was used. The amphetamine was injected subcutaneously at a dosage of 2.5 mglkg; the Tofranil was administered orally at dosages of 10 and 25 mg/kg or the new compound orally at a dosage of 10 mg/kg. The number of mice in each experimental series is shown in Table IV. In order to measure the motor activity the mouse was placed in a rectangular (25 cm X l5 cm) Plexiglass" cage through which two crossed infrared beams pass; the beams are interrupted when the animals move, and these interruptions were recorded by a photoelectric device and a calculator; the number ofinterruptions during the period of time selected was taken as a measure of the motor activity. This motor activity was measured for two successive periods of 5 minutes; the mice were placed in the cage 60 minutes afler ingestion of the Tofranil of the new compound, and minutes after the amphetamine had been injected. The results are shown in Table IV below.

Neither the compound of the invention nor Tofranil affected the exploratory motor activity (attributable to the searching instinct of the animal) observed between 0 and 5 minutes, on the other hand, the two compounds reduced the basic motor activity, that compound of the invention being greater than that of Tot'ranil, for comparable posology.

The compound of the invention, at dosages of 10 mg/kg. reduced the motor activity of the mice which had received the amphetamine. It is, above all, the efl'ect observed between 0 and 5 minutes which allows one to conclude that a reduction in hyperactivity has been caused. At a dosage of 10 mg/kg Tofranil was ineflective; at a dosage of 25 rug/kg a reduction of motor activity (compared to a group which had only received the amphetamine) was only observed between 0 and 5 minutes. Thus the compound of the invention has the same type of activity as that of Tofranil but for comparable osology its effect is greater.

The compound of the invention thus has thymoleptic propertiea which, on the one hand, make for a preservation of the searching instinct of the mouse at a strongly reduced basic motor activity and, on the other hand, for a reduction of the hyperactivity released by the amphetamine.

Pharmacological experiments showed that the new compound is less toxic that Tofranil, whose DL 50 for rats, when administered orally, is 625 mglkg.

When used in human beings as a thymoleptic agent the compound according to the invention may be administered:

Either dissolved in an appropriate solvent in a dosage unit form such as injectable and drinkable ampoules, syrup;

Or in the solid state in a dosage unit form such as tablets,

capsules, cachets, granules su positories. The dosage unit is approximate y 50 mg. and the total daily dose to be administered is inferior to or equals 500 mg.

I claim: I. A pharmaceutical composition having a thymoleptic effect comprising as the active ingredient N-[3,4-di(alkoxycarbonyl)cinnamyl]-iminodibenzyl of the formula:

wherein R is a lower alkyl group, or a non-toxic acid addition salt thereof and a pharmaceutically acceptable carrier, the ac tive ingredient being present in a concentration and amount sufficient to exert an anti-depressant effect.

2. The composition of claim I wherein the compound is N- 3,4-[di(ethoxycarb0nyl)-cinnamyl]-iminodibenzyl or a nontoxic acid addition salt thereof.

3. The composition of claim 1 wherein the active ingredient is present in an amount from about 50 to 500 mg.

4. A method of treating patients sufiering from depression comprising administering to said patients a thymoleptic composition comprising as the active ingredient N-[3,4-di(alkoxycarbonyl)-cinnamyl]-iminodibenzyl of the formula CHz-CH 5. The method of claim 4 wherein the active compound is N-3,4-[di( ethoxycarbonyl )-cinnamyl l-iminodibenzyl.

e e 1: e V n 

2. The composition of claim 1 wherein the compound is N-3,4-(di(ethoxycarbonyl)-cinnamyl)-iminodibenzyl or a non-toxic acid addition salt thereof.
 3. The composition of claim 1 wherein the active ingredient is present in an amount from about 50 to 500 mg.
 4. A method of treating patients suffering from depression comprising administering to said patients a thymoleptic composition comprising as the active ingredient N-(3,4-di(alkoxycarbonyl)-cinnamyl)-iminodibenzyl of the formula
 5. The method of claim 4 wherein the active compound is N-3,4-(di(ethoxycarbonyl)-cinnamyl)-iminodibenzyl. 